tbuckley/cabot-search huggingface dataset:
Pregnancy and neonatal outcomes in women with axial spondyloarthritis: pooled data analysis from the European Network of Pregnancy Registries in Rheumatology (EuNeP)
Authors: Yvette Meissner, Anja Strangfeld, Anna Molto, Frauke Forger, Marianne Wallenius, Nathalie Costedoat-Chalumeau, Hilde Bjørngaard, Marion Couderc, René-Marc Flipo, Gaëlle Guettrot-Imbert, Isabell Haase, Bente Jakobsen, Hege Suorza Svean Koksvik, Christophe Richez, Jérémie Sellam, Anja Weiß, Astrid Zbinden, Rebecca Fischer-Betz
Journal: Annals of the Rheumatic Diseases (2022)

Objective To investigate outcome and course of pregnancies in women with axial spondyloarthritis (axSpA) in a pooled data analysis of pregnancy registries in rheumatology. Methods Prospectively followed women with axSpA, fulfilling ASAS classification criteria and for whom a pregnancy outcome was reported, were eligible for the analysis. Anonymised data of four registries was pooled. Rates of adverse pregnancy outcomes were calculated. Systemic inflammation, disease activity and treatment patterns with tumour necrosis factor inhibitor (TNFi) before, during and after pregnancy were analysed. Results In a total of 332 pregnancies from 304 axSpA women, 98.8% of the pregnancies resulted in live birth. Mean maternal age was 31 years and disease duration 5 years. Most of these patients received pre-conception counselling (78.4%). Before pregnancy, 53% received TNFi treatment, 27.5% in first and 21.4% in third trimester. Pregnancy and neonatal outcomes were favourable with rates of 2.2% for pre-eclampsia, 4.9% for preterm birth, 3.1% for low birth weight and 9.5% for small for gestational age. Neonates were delivered by caesarean section in 27.7% of pregnancies, of which 47.4% were emergencies. Pooled mean CRP was 4 mg/L before conception peaking in the second trimester at 9.4 mg/L. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was below 4 at all time-points. Conclusions Pooled rates of most outcomes were better than what had been reported in the literature and within expected rates of those reported for the general population. Pre-conception counselling, planned pregnancies and a tight management in expert centres applying a tailored treatment approach may have contributed to the favourable pregnancy outcomes.
When I use a word . . . . Too much healthcare—overdefinition
Authors: Jeffrey K Aronson
Journal: BMJ (2022)

Overdefinition is one of two major factors that contribute to overdiagnosis in medical practice. Overdefinition has several different meanings, depending on the topic. In linguistics it describes attribution of more than one apparent meaning, depending on context, to a word that means only a single thing. In mathematics it can refer to a property of simultaneous equations in which the equations outnumber the variables or to models in which there are more variables than expressions or sources of measurement for them. In business management it occurs either when a new product line is added, being then regarded as a completely new business, or when excessively precise instructions about how a business should be run are laid down. And in legislation it occurs when the legislator frames the text in such a way as to cover every possible eventuality, more often resulting in ambiguity than clarity. Medical overdefinition occurs when the threshold for a risk factor that defines a disorder is altered, typically downward, from some previous value, the treatment of which confers benefit, widening the scope of the disorder, or when disease definitions are expanded to include patients with ambiguous or very mild symptoms. Possible solutions to the problem of medical overdefinition include framing definitions carefully, specifying their repeatability, reproducibility, and accuracy, prediction of the ways in which the incidence and prevalence of disorders are likely to change with overdefinition, identification of the triggers that lead to overdefinition, and analysis of the resulting benefits, harms, and benefit to harm balance.
Physical activity paradox: could inflammation be a key factor?
Authors: Joshua Buron Feinberg, Anne Møller, Volkert Siersma, Helle Bruunsgaard, Ole Steen Mortensen
Journal: British Journal of Sports Medicine (2022)

Objective The aim of this study was to test the extent to which physical activity performed during work and leisure is associated with systemic inflammation. Methods Data regarding job history and high-sensitivity C reactive protein (hs-CRP) levels, as well as potential confounders, came from the Copenhagen Aging and Midlife Biobank. The participants’ self-reported job history was combined with a job exposure matrix to give a more valid assessment of cumulated occupational physical activity compared with conventional self-reported activity. Occupational physical activity was measured as cumulative ton-years (lifting 1000 kg each day for a year). Current leisure time physical activity was self-reported into four different categories. We analysed the association between occupational physical activity, current leisure time physical activity and hs-CRP level in a multivariable linear regression model with adjustment for age, sex, smoking history, number of chronic diseases, body mass index and alcohol. Results In unadjusted analysis, higher occupational physical activity was associated with increased hs-CRP levels, while higher leisure time physical activity was associated with lower hs-CRP levels. In adjusted analysis, lower leisure time physical activity resulted in 12% higher hs-CRP levels while higher occupational physical activities showed a 6% increase in hs-CRP. When we analysed occupational and leisure time physical activity as continuous variables, only leisure time physical activity affected hs-CRP. Conclusion This study indicates that the relationship between physical activity and hs-CRP depends on the setting of physical activity, with lower hs-CRP related to leisure time physical activity and higher hs-CRP related to occupational physical activity. The results suggest that systemic inflammation may explain the physical activity paradox.
A stable DNA Tetrahedra–AuNCs nanohybrid: On-site programmed disassembly for tumor imaging and combination therapy
Authors: Huanhuan Sun, Tianzheng Wang, Wenjie Ma, Jin Huang, Biao Chen, Hong Cheng, Shuangdi Duan, Xiaoxiao He, Lixin Jian, Kemin Wang
Journal: Biomaterials (2022)
Prevalence of and factors associated with osteoarthritis and pain in retired Olympians compared with the general population: part 2 – the spine and upper limb
Authors: Debbie Palmer, Dale Cooper, Jackie L Whittaker, Carolyn Emery, Mark E Batt, Lars Engebretsen, Patrick Schamasch, Malav Shroff, Torbjørn Soligard, Kathrin Steffen, Richard Budgett
Journal: British Journal of Sports Medicine (2022)

(1) To determine the prevalence of spine and upper limb osteoarthritis (OA) and pain in retired Olympians; (2) identify risk factors associated with their occurrence and (3) compare with a sample of the general population.
Programmed prodrug breaking the feedback regulation of P-selectin in plaque inflammation for atherosclerotic therapy
Authors: Quan Wang, Hongshu Jing, Jun Lin, Zhihua Wu, Yu Tian, Ke Gong, Qianqian Guo, Xupeng Yang, Liting Wang, Zhaojun Li, Yourong Duan
Journal: Biomaterials (2022)
Immunodeficiency, autoimmunity, and increased risk of B cell malignancy in humans with <i>TRAF3</i> mutations
Authors: William Rae, John M. Sowerby, Dorit Verhoeven, Mariam Youssef, Prasanti Kotagiri, Natalia Savinykh, Eve L. Coomber, Alexis Boneparth, Angela Chan, Chun Gong, Machiel H. Jansen, Romy du Long, Giorgia Santilli, Ilenia Simeoni, Jonathan Stephens, Kejia Wu, Marta Zinicola, Hana Lango Allen, Helen Baxendale, Dinakantha Kumararatne, Effrossyni Gkrania-Klotsas, Selma C. Scheffler Mendoza, Marco Antonio Yamazaki-Nakashimada, Laura Berrón Ruiz, Cesar Mauricio Rojas-Maruri, Saul O. Lugo Reyes, Paul A. Lyons, Anthony P. Williams, Daniel J. Hodson, Gail A. Bishop, Adrian J. Thrasher, David C. Thomas, Michael P. Murphy, Timothy J. Vyse, Joshua D. Milner, Taco W. Kuijpers, Kenneth G. C. Smith
Journal: Science Immunology (2022)

Tumor necrosis factor receptor–associated factor 3 (TRAF3) is a central regulator of immunity. TRAF3 is often somatically mutated in B cell malignancies, but its role in human immunity is not defined. Here, in five unrelated families, we describe an immune dysregulation syndrome of recurrent bacterial infections, autoimmunity, systemic inflammation, B cell lymphoproliferation, and hypergammaglobulinemia. Affected individuals each had monoallelic mutations in TRAF3 that reduced TRAF3 expression. Immunophenotyping showed that patients’ B cells were dysregulated, exhibiting increased nuclear factor-κB 2 activation, elevated mitochondrial respiration, and heightened inflammatory responses. Patients had mild CD4 + T cell lymphopenia, with a reduced proportion of naïve T cells but increased regulatory T cells and circulating T follicular helper cells. Guided by this clinical phenotype, targeted analyses demonstrated that common genetic variants, which also reduce TRAF3 expression, are associated with an increased risk of B cell malignancies, systemic lupus erythematosus, higher immunoglobulin levels, and bacterial infections in the wider population. Reduced TRAF3 conveys disease risks by driving B cell hyperactivity via intrinsic activation of multiple intracellular proinflammatory pathways and increased mitochondrial respiration, with a likely contribution from dysregulated T cell help. Thus, we define monogenic TRAF3 haploinsufficiency syndrome and demonstrate how common TRAF3 variants affect a range of human diseases.
Signatures of recent activation identify a circulating T cell compartment containing tumor-specific antigen receptors with high avidity
Authors: Anna Purcarea, Sebastian Jarosch, Jack Barton, Simon Grassmann, Ludwig Pachmayr, Elvira D’Ippolito, Monika Hammel, Anna Hochholzer, Karolin I. Wagner, Joost H. van den Berg, Veit R. Buchholz, John B. A. G. Haanen, Dirk H. Busch, Kilian Schober
Journal: Science Immunology (2022)

T cell receptor (TCR) avidity is assumed to be a major determinant of the spatiotemporal fate and protective capacity of tumor-specific T cells. However, monitoring polyclonal T cell responses with known TCR avidities in vivo over space and time remains challenging. Here, we investigated the fate and functionality of tumor neoantigen-specific T cells with TCRs of distinct avidities in a well-established, reductionist preclinical tumor model and human patients with melanoma. To this end, we used polyclonal T cell transfers with in-depth characterized TCRs together with flow cytometric phenotyping in mice inoculated with MC38 OVA tumors. Transfer of T cells from retrogenic mice harboring TCRs with high avidity resulted in best tumor protection. Unexpectedly, we found that both high- and low-avidity T cells are similarly abundant within the tumor and adopt concordant phenotypic signs of exhaustion. Outside the tumor, high-avidity TCR T cells were not generally overrepresented but, instead, selectively enriched in T cell populations with intermediate PD-1 protein expression. Single-cell sequencing of neoantigen-specific T cells from two patients with melanoma-combined with transgenic reexpression of identified TCRs by CRISPR-Cas9-mediated orthotopic TCR replacement-revealed high-functionality TCRs to be enriched in T cells with RNA signatures of recent activation. Furthermore, of 130 surface protein candidates, PD-1 surface expression was most consistently enriched in functional TCRs. Together, our findings show that tumor-reactive TCRs with high protective capacity circulating in peripheral blood are characterized by a signature of recent activation.
Pan-cancer efficacy of pralsetinib in patients with RET fusion–positive solid tumors from the phase 1/2 ARROW trial
Authors: Vivek Subbiah, Philippe A. Cassier, Salvatore Siena, Elena Garralda, Luis Paz-Ares, Pilar Garrido, Ernest Nadal, Jacqueline Vuky, Gilberto Lopes, Gregory P. Kalemkerian, Daniel W. Bowles, Mahesh Seetharam, Jianhua Chang, Hui Zhang, Jennifer Green, Alena Zalutskaya, Martin Schuler, Yun Fan, Giuseppe Curigliano
Journal: Nature Medicine (2022)

Abstract Oncogenic RET fusions occur in diverse cancers. Pralsetinib is a potent, selective inhibitor of RET receptor tyrosine kinase. ARROW ( NCT03037385 , ongoing) was designed to evaluate pralsetinib efficacy and safety in patients with advanced RET -altered solid tumors. Twenty-nine patients with 12 different RET fusion–positive solid tumor types, excluding non-small-cell lung cancer and thyroid cancer, who had previously received or were not candidates for standard therapies, were enrolled. The most common RET fusion partners in 23 efficacy-evaluable patients were CCDC6 (26%), KIF5B (26%) and NCOA4 (13%). Overall response rate, the primary endpoint, was 57% (95% confidence interval, 35–77) among these patients. Responses were observed regardless of tumor type or RET fusion partner. Median duration of response, progression-free survival and overall survival were 12 months, 7 months and 14 months, respectively. The most common grade ≥3 treatment-related adverse events were neutropenia (31%) and anemia (14%). These data validate RET as a tissue-agnostic target with sensitivity to RET inhibition, indicating pralsetinib’s potential as a well-tolerated treatment option with rapid, robust and durable anti-tumor activity in patients with diverse RET fusion–positive solid tumors.
Comparative efficacy and acceptability of psychotherapies, pharmacotherapies, and their combination for the treatment of adult insomnia: A systematic review and network meta-analysis
Authors: Ye Zhang, Rong Ren, Linghui Yang, Haipeng Zhang, Yuan Shi, Jie Shi, Larry D. Sanford, Lin Lu, Michael V. Vitiello, Xiangdong Tang
Journal: Sleep Medicine Reviews (2022)
Predicting probability of tolerating discrete amounts of peanut protein in allergic children using epitope‐specific <scp>IgE</scp> antibody profiling
Authors: Maria Suprun, Paul Kearney, Clive Hayward, Heather Butler, Robert Getts, Scott H. Sicherer, Paul J. Turner, Dianne E. Campbell, Hugh A. Sampson
Journal: Allergy (2022)

Abstract Background IgE‐epitope profiling can accurately diagnose clinical peanut allergy. Objective We sought to determine whether sequential (linear) epitope‐specific IgE (ses‐IgE) profiling can provide probabilities of tolerating discrete doses of peanut protein in allergic subjects undergoing double‐blind, placebo‐controlled food challenges utilizing PRACTALL dosing. Methods Sixty four ses‐IgE antibodies were quantified in blood samples using a bead‐based epitope assay. A pair of ses‐IgEs that predicts Cumulative Tolerated Dose (CTD) was determined using regression in 75 subjects from the discovery cohort. This epitope‐based predictor was validated on 331 subjects from five independent cohorts (ages 4–25 years). Subjects were grouped based on their predicted values and probabilities of reactions at each CTD threshold were calculated. Results In discovery, an algorithm using two ses‐IgE antibodies was correlated with CTDs (rho = 0.61, p &lt; .05); this correlation was 0.51 ( p &lt; .05) in validation. Using the ses‐IgE‐based predictor, subjects were assigned into “high,” “moderate,” or “low” dose‐reactivity groups. On average, subjects in the “high” group were four times more likely to tolerate a specific dose, compared with the “low” group. For example, predicted probabilities of tolerating 4, 14, 44, and 144 or 444 mg in the “low” group were 92%, 77%, 53%, 29%, and 10% compared with 98%, 95%, 94%, 88%, and 73% in the “high” group. Conclusions Accurate predictions of food challenge thresholds are complex due to factors including limited responder sample sizes at each dose and variations in study‐specific challenge protocols. Despite these limitations, an epitope‐based predictor was able to accurately identify CTDs and may provide a useful surrogate for peanut challenges.
Single-cell ATAC-seq maps the comprehensive and dynamic chromatin accessibility landscape of CAR-T cell dysfunction
Authors: Penglei Jiang, Zhaoru Zhang, Yongxian Hu, Zuyu Liang, Yingli Han, Xia Li, Xin Zeng, Hao Zhang, Meng Zhu, Jian Dong, He Huang, Pengxu Qian
Journal: Leukemia (2022)
Prognostic impact of <i>NPM1</i> and <i>FLT3</i> mutations in patients with AML in first remission treated with oral azacitidine
Authors: Hartmut Döhner, Andrew H. Wei, Gail J. Roboz, Pau Montesinos, Felicitas R. Thol, Farhad Ravandi, Hervé Dombret, Kimmo Porkka, Irwindeep Sandhu, Barry Skikne, Wendy L. See, Manuel Ugidos, Alberto Risueño, Esther T. Chan, Anjan Thakurta, C.L. Beach, Daniel Lopes de Menezes
Journal: Blood (2022)

The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
Early-Phase Oncology Trials: Why So Many Designs?
Authors: Matthieu Clertant
Journal: Journal of Clinical Oncology (2022)

The past 30 years have seen a considerable effort on the part of statisticians to improve the design and accuracy of early-phase oncology trials. Some of this effort has been rewarded via successful implementation in actual trials, yet it would be fair to say that among clinicians, there remains some reluctance to fully embrace more efficient model-based approaches. One reason for such reticence is the difficulty in understanding exactly what is being offered by more modern designs. Although it is generally accepted that these designs offer improvements over the old standard 3 + 3 design, a new question has then to be addressed: How should we decide among the new proposals which one is the best for our purpose? In this study, we recall 15 designs that are currently proposed and in use. We show that among these 15 designs, many are operationally identical. These 15 designs reduce to three broad classes of designs. This review helps summarize their properties and differences and highlights that certain designs require ad hoc modifications to ensure satisfactory performance.
Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial
Authors: Meletios A. Dimopoulos, Dominik Dytfeld, Sebastian Grosicki, Philippe Moreau, Naoki Takezako, Mitsuo Hori, Xavier Leleu, Richard LeBlanc, Kenshi Suzuki, Marc S. Raab, Paul G. Richardson, Mihaela Popa McKiver, Ying-Ming Jou, David Yao, Prianka Das, Jesús San-Miguel
Journal: Journal of Clinical Oncology (2022)

In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results.Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically.A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected.EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.